Diabetes is a disease with chronic hyperglycemia as a cardinal sign and develops by absolute or relative deficiency of insulin activity. Clinically, diabetes is roughly classified by the characteristic into insulin-dependent diabetes (referred to as “Type 1 diabetes” hereinafter) and non-insulin-dependent diabetes (referred to as “Type 2 diabetes” hereinafter). In Type 2 diabetes, which accounts for approximately 90% of diabetic patients, decrease of insulin secretion from the pancreatic β-cells is one of major causes of the onset, and postprandial hyperglycemia caused by early disorder in insulin secretion is particularly recognized. Presently, sulfonylurea drug (SD drug) is the mainstream as the insulin secretagogue, but it is likely to cause hypoglycemia and known to cause secondary ineffectiveness due to pancreatic exhaustion following long-term administration. Moreover, SU drug is effective to control blood glucose between meals, but has difficulty in suppressing postprandial hyperglycemia. Recent large-scale clinical trials have confirmed that remedying postprandial hyperglycemia is critical in controlling diabetic complications and diabetic development (non-patent document 1). It is also reported that arteriosclerosis develops only during periods of the postprandial hyperglycemia and that the persistence of minor postprandial hyperglycemia increases mortality caused by cardiovascular disease or the like. (non-patent document 2 and 3). This indicates that postprandial hyperglycemia is, even at minor levels, an independent risk factor of cardiovascular death. From the above background, attention has been paid to importance and necessity for medications against postprandial hyperglycemia. Hence, drugs having promoting activity on insulin secretion are considered to have an appropriate profile to remedy postprandial hyperglycemia and/or fasting blood glucose and to be useful for treating and preventing of Type 1 and Type 2 diabetes.
WO 2004/065391 pamphlet (patent document 1) discloses thiophene-fused pyrimidine derivatives substituted with a cyano group as phosphodiesterase 7 (PDE 7) inhibitors and describes Type 1 and Type 2 diabetes as examples of diseases that are expected to be improved by inhibition of PDE 7. However, neither compounds of the present invention are specifically disclosed, nor are specific data indicating their applicability to diabetes therapy such as promoting activity on insulin secretion.
In WO 03/049739 pamphlet (patent document 2) discloses fused pyrimidine derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors and describes diabetes as an example of diseases for which these compounds are useful, that is, diseases caused by action of GSK-3. However, none of compounds of the present invention are specifically disclosed therein, and there are not disclosed specific data indicating their applicability of said compounds to diabetes therapy such as promoting activity on insulin secretion, either.
WO 2005/032481 pamphlet (patent document 3) discloses fused pyrimidine derivatives as Transforming growth factor-beta (TGFβ) inhibitors, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
WO 2004/087056 pamphlet (patent document 4) discloses fused pyrimidine derivatives as Transforming growth factor-beta (TGFβ) inhibitors, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
WO 03/097615 pamphlet (patent document 5) discloses fused pyrimidine derivatives as Transforming growth factor-beta (TGFβ) inhibitors but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
WO 2004/014850 pamphlet (patent document 6) discloses 5-membered aromatic heterocycle fused pyrimidine derivatives as neurokinin antagonists, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
US Patent Publication U.S. Pat. No. 4,196,207 (patent document 7) discloses thiophene-fused pyrimidine derivatives as miticides, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
US Patent Publication U.S. Pat. No. 4,146,716 (patent document 8) discloses thiophene-fused pyrimidine derivatives as antifungal agents, antiviral agents and pesticides, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
Furthermore, thiephene-fused pyrimidine derivatives and pyridine-fused pyrimidine derivatives are disclosed in the literature relating to synthetic organic chemistry (non-patent document 4 and 5).    non-patent document 1: N. Engl. J. Med., 329: 977-986, 1993    non-patent document 2: Lancet, 354: 617, 1999    non-patent document 3: Brit. Med. J., 321: 405-413, 2000    non-patent document 4. Bulletin de la Societe Chimique de France, 3-4(PT.2), 815-819, 1975    non-patent document 5: Annales Pharmaceutiques Francaises, 32(11), 575-579, 1974    patent document 1: WO 2004/065391    patent document 2: WO 03/049739    patent document 3: WO 2005/032481    patent document 4: WO 2004/087056    patent document 5: WO 03/097615    patent document 6: WO 2004/014850    patent document 7: U.S. Pat. No. 4,196,207    patent document 8: U.S. Pat. No. 4,146,716